In a rare pair of papers published back-to-back in the journal Genes & Development, research teams led by senior author Anindya Bagchi, PhD, associate professor in the Cancer Genome and Epigenetics Programme at Sanford Burnham Prebys Medical Discovery Institute, establish a unified framework that governs one of cancer’s most powerful master regulators.

The MYC gene is among the most frequently altered driver genes in human cancer, with its deregulation implicated  in more than half of all cases.

It acts as a master regulator controlling cell growth, division and metabolism.

When overactive, MYC forces cells into rapid, uncontrolled tumour growth and drives aggressive, treatment-resistant cancers across virtually all tumour types, from solid tumours like breast and lung to blood cancers like leukaemia.

Historically, MYC has been considered “undruggable” because the MYC protein lacks the typical binding pockets targeted by traditional small-molecule drugs, leaving clinicians with few direct ways to shut down MYC‑driven tumours.

“These paired, back-to-back publications tell a remarkable story about untangling a long-standing mystery in cancer biology, a mystery I tried to solve as part of my own PhD two decades ago!,” said Paul Boutros, PhD, MBA, director of the National Cancer Institute-designated cancer centre at Sanford Burnham Prebys.

“It’s an incredible achievement by Dr. Bagchi, and really reflects the calibre and impact of discovery science that defines our cancer centre.”

The new studies focus on a region adjacent to MYC on human chromosome 8q24, known as the Plasmocytoma Variant Translocation 1 (PVT1) locus.

Previous work in the Bagchi lab had shown that PVT1 is essential for MYC-driven tumour growth, but the mechanism was unknown.

The paired papers solve this puzzle with an unexpected answer: PVT1 is an active regulatory hub for MYC activity encoding two novel proteins that play key roles in enabling MYC in these cancers.

“These two studies show that you do not have to hit MYC directly to control MYC‑driven cancers,” said Bagchi.

“By uncovering key molecules that MYC depends on, we are opening up a new set of therapeutic entry points for tumours that have long been considered beyond the reach of targeted therapies.”

In the first paper, published on August 19, 2026, in Genes & Development, Bagchi and colleagues focused on PVT1, until now considered a long non-coding RNA adjacent to MYC and frequently co-amplified with MYC in many cancers.

Previous research had shown PVT1 increases MYC activity, but the new study revealed that PVT1 does so by generating a circular RNA (CircPVT1) that encodes a novel protein the researchers named Firefox and which they determined is essential for MYC-mediated oncogenic signalling—the cascade of molecular events that drive the uncontrolled growth, survival and spread of cancer cells.

When researchers depleted Firefox, MYC protein abundance and transcriptional output declined.

In animal models of MYC-driven cancers, induced depletion of Firefox significantly impaired tumour growth.

“Firefox behaves like a critical helper that MYC needs in order to fully transform a cell into a cancer cell,” Bagchi said.

“If you remove Firefox, MYC loses much of its power, which makes Firefox a very attractive potential drug target in MYC‑driven tumours.”

In the second paper, also published in Genes & Development, Bagchi and colleagues examined a second kind of structural rearrangement at PVT1, and discovered that a segment of PVT1 is consistently deleted due to translocation, which happens with a segment of DNA breaks away from one chromosome and attaches to a different chromosome.

The researchers found that the affected segment encodes a novel micropeptide, which they dubbed Honeybadger.

The micropeptide, they said, acts as a built-in brake on cancer growth.

Honeybadger directly binds KRAS—a key signalling protein in cancer.

Mutated forms of KRAS are major drivers of tumour growth and are implicated in roughly 25 to 30% of all human cancers.

By binding KRAS, Honeybadger dampens the RAS‑MAPK signalling pathway under normal conditions.

When PVT1translocations delete the Honeybadger-encoding region, the brake is removed, allowing wild-type KRAS to hyperactivate MAPK signalling.

This in turn stabilises MYC protein and amplifies its cancer-driving output – even in tumours that lack KRAS mutations.

The result is a dual hit: gain of the Firefox oncoprotein and loss of the Honeybadger tumour suppressor, which synergistically boosts MYC output and helps explain the particularly poor prognosis of PVT1‑rearranged cancers.

“The surprising lesson from these two papers is that PVT1 is not just a passive neighbour of MYC. It is an active regulatory hub that can either fuel or restrain MYC‑driven cancers, depending on which of its products are present,” Bagchi said.

“Together, the papers establish a “dual-hit” mechanism: a single structural alteration at PVT1 simultaneously preserves an oncogene (Firefox) and eliminates a tumour suppressor (Honeybadger), with both changes converging to amplify MYC activity. This makes PVT1 and its encoded proteins an especially rich source of new biomarkers and potential therapeutic targets.”

Bagchi said the research team next plans to investigate how Firefox and Honeybadger behave in additional cancer types and to work with collaborators to begin developing prototype therapeutic strategies.

“Our goal is to translate these basic discoveries into first‑in‑class therapeutic approaches that could ultimately benefit patients with MYC‑driven tumours, which currently have very limited targeted treatment options,” he said.

Source: Sanford Burnham Prebys